Elisa Vigna, Ph.D.
Development and validation of cancer immunotherapy strategies based on MET antibody and MET antibody-derived molecules.
Clinical evidence indicates that the MET oncogene plays a role in progression of cancer toward metastasis and/or resistance to targeted therapies. While mutations are rare, the common mechanism of MET activation is overexpression, either by gene amplification (‘addiction’) or transcriptional activation (‘expedience’). In both instances ligandindependent kinase activation plays the major role in sustaining the transformed phenotype. Currently available MET antibodies are directed against the receptor binding site, behaving essentially as a ligand (HGF) antagonist, and are ineffective in ligand-independent activation.
The monovalent chimeric MvDN30 antibody, delivered as a purified protein, binds the extracellular domain and induces the proteolytic cleavage of MET, dramatically inhibiting downstream signaling pathways, in both the absence or presence of ligand. MvDN30 has the limit of poor in vivo stability. To address this issue MvDN30 was delivered by ‘gene therapy’, to induce a stable and constant in vivo production that counterbalances the high rate of clearance. As alternatives, the molecule has also been chemically modified (i.e. Pegylated) or engineered, including two repetitions of the constant domain (DCD). All the explored strategies led to the improvement of the MvDN30 potency. By the gene therapy approach, direct Mv-DN30 gene transfer in nude mice, intra-tumor or systemic, was followed by a therapeutic response of MET addicted human glioblastomas and lung carcinomas. Upon Pegylation the antibody overcame the resistance to EGFR targeted therapy in a MET-amplified patient-derived colorectal tumor (xenopatient). The DCD approach was successfully applied to inhibit the peritoneal carcinomatosis of a MET-addicted gastric tumor.
Conclusions and perspectives:
We developed strategies suitable to improve the potency of MvDN30, rendering it an attractive candidate for clinical applications. To further enlarge the panel of anti-MET immunotherapy routes we aim to explore a strategy of re-directed adoptive immune response by a Chimeric Antigen Receptor anti-Met.